Readers will recall, that once-weekly injections of the novel long-acting GLP-1 analogue semaglutide was recently shown (in patients with type 2 diabetes) to result in a rather impressive weight loss.
Now, a phase II dose-finding study comparing various oral doses of semaglutide to subcutaneous injections in patients with type 2 diabetes was just published in JAMA.
The 26-week trial with 5-week follow-up included around 600 patients with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized to once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.
Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%);
Significant reductions were also seen in body weight with both oral (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg)>
Adverse events (largely consisting of mild to moderate gastrointestinal events) were as expected and relatively comparable between the treatment arms.
Although this was a diabetes study, these findings clearly hold promise for the further development of an oral formulation of semaglutide for the obesity indication.
Disclaimer: I have served as a consultant for Novo Nordisk, the maker of semaglutide.
A recent CMAJ article, by Ian Mosby and Tracey Galloway from the University of Toronto argues that one of the key reasons why we see obesity and diabetes so rampant in Canada’s indigenous populations, is the fact that widespread and persistent exposure to hunger during the notorious residential school system may have metabolically “programmed” who generations toward a greater propensity for obesity and type 2 diabetes.
There is indeed a very plausible biological hypothesis for this,
“Hunger itself has profound consequences for childhood development. Children experiencing hunger have an activated hypothalamic–pituitary–adrenal stress response. This causes increased cortisol secretion which, over the long term, blunts insulin response, inhibits the function of insulin-like growth factor and produces long-term changes in lipid metabolism. Through this process, the child’s physiology is essentially “programmed” by hunger to continue the cycle of worsening effects, with their bodies displaying a rapid tendency for fat-mass accumulation when nutritional resources become available.”
While the impact of hunger may well have been one of the key drivers or metabolic changes, the authors failed to acknowledge another (even more?) important consequence of residential schools – the impact on mental health.
Oddly enough, in a blog post I wrote back in 2008, I discussed the notion that the significant (and widespread) physical, emotional, and sexual abuse experienced by the generations of indigenous kids exposed to the residential school system would readily explain much of the rampant psychological problems (addictions, depression, PTSD, etc.) present in the indigenous populations across Canada today.
The following is an excerpt from this previous post:
This disastrous and cruel [residential school] policy resulted in much pain and despair in the First Nations’, Inuit and Metis people that lasts to this day (known as the “generational effect”). Sexual, physical and mental abuse was widespread; students were broken in heart and spirit; culture and identities were destroyed.
Much (if not all) of what ails the Aboriginal peoples of Canada can be traced back to this policy – including possibly issues that affect Aboriginal health to this day.
It is no secret that obesity and its consequences (e.g. diabetes) are rampant amongst the Aboriginal peoples of Canada. While poverty, breakdown of traditional lifestyle and culture and even genetic factors (thrifty genotype) have all been implicated in this, I wonder how much the misery caused by the residential school program had to contribute.
Early traumatic life experiences including sexual, mental and physical abuse as well as neglect and grief have all been implicated in binge eating disorder (BED) – in its purest form – the uncontrollable urge to devour large quantities of highly palatable high-caloric foods in response to emotional hunger. This behaviour has been interpreted as an emotional coping strategy, “filling the inner void”, building a physical protective barrier, etc., the ultimate result being excessive weight gain with all its consequences (the typical binger does not compensate by purging or excessive exercise).
In “treatment-seeking” patients with obesity, the prevalence of BED is estimated at 20-40%. Although I was unable to find a study that has applied the DSM-IV criteria for BED to an Aboriginal population – my guess is: the rates are probably high!
Given its distinct psychopathology, BED is highly responsive to psychotherapeutic approaches. In contrast, educational initiatives based on simply providing information on healthy lifestyles are useless.
Obesity is never an issue of “choice”. I have yet to meet anyone who “chooses” to be obese. This is most certainly also true for Canada’s Aboriginal population.”
Managing weight in patients with type 2 diabetes (most of who have significant overweight or obesity) is always challenging, not least because many medications used to treat diabetes can also promote weight gain.
Now, a paper by Judy Shiau and colleagues from the University of Ottawa, in a paper published in the Canadian Journal of Diabetes, present the results of a retrospective cohort study (1992 to 2009) of weight, glycemic control and diabetes medications changes in 317 patients with obesity and type 2 diabetes at 6 months on a low-calorie diet program.
The program (week 1 to week 26) included mandatory weekly group sessions led by a dietitian, behaviour therapist or exercise therapist. All patients received OPTIFAST ®900 as full meal replacements (MR) starting at week 2. Patients consume 4 MR shakes per day for a total of 900 kcal per day, a regimen that is high in proteins (90g/day) and moderate in carbohydrates (67 g/day). Patients with initial body mass indexes (BMIs) of 33 kg/m2 or higher commited to 12 weeks of full MRs, while patients with initial BMIs below 33 started with 6 weeks of full MRs and the option to increase to up to 12 weeks of full MRs. Once patients completed their full MR regimen, there was a 5-week transition period to regular food, typically followed by a maintenance diet, as determined in a one-on- one dietitian counselling session.
As glycemic control improved with weight loss, anti-diabetes medications were adjusted or discontinued, thereby stopping any weight-gain-promoting medications first.
As the authors note,
“At 6 months, both groups had lost 16% of their weight, and the decreases or discontinuations of medications were 92% sulfonureas, 87% insulins, 79% thiazolidinediones, 78% alpha-glucosidase inhibitors, 50% meglitinides, 33% dipeptidyl peptidase-4 (DPP-4) inhibitors and 33% metformin. At 6 months, compared with baseline, A1C levels improved significantly and at 6 months, 30% of patients were no longer taking diabetes medications and had significantly better percentages of weight loss compared with those taking medications (18.6% vs. 16%; p=0.002).”
Thus, this paper shows that, a low-calorie meal replacement program can substantially improve glycemic control and reduce the need for anti-diabetes medications.
Unfortunately, as participants were transitioned to community care at 6 months, little is know about how long these effects last.
Nevertheless, with the increasing availability and use of weight-neutral or even weight-reducing anti-diabetes medications, one may expect that some of these effects can be sustained for relevant periods of time.
Last week I was an invited plenary speaker at the 1st International Diabetes Expert Conclave (IDEC2017) held in Pune, India.
This 3-day event, organised by Drs. Neeta Deshpande (Belgaum), Sanjay Agrawal (Pune) and colleagues, brought together well over 900 physicians from across India for a jam-packed program that covered everything from diabetic food disease and neuropathy to the latest in insulin pumps and devices – all in a uniquely Indian context.
I, of course, was there to speak on obesity, which featured prominently in the program. Topics on obesity ranged from the potential role of gut bugs to bariatric surgery. While Dr. Allison Goldfine, former Director of Clinical Research at the Joslin Diabetes Center in Boston spoke on the latest developments in anti-obesity pharmacotherapy (delivering her talk via Skype), I spoke about obesity as a chronic disease and the need to redefine obesity based on actual indicators of health rather than BMI.
During my visit in Pune, I also had the opportunity to visit with my friend and colleague Dr. Shashank Shah, whose bariatric surgical center in Pune alone performs about 75 to 100 bariatric operations per month – a remarkable number by any standards.
Of course, the overwhelming number of talks were given by Indian faculty (there being only a handful of select invited international faculty at the meeting), and I did come away most impressed by the breadth and depth of knowledge presented by the local speakers.
Diabetes care certainly appears to be in good hands although the sheer number of patients with diabetes (estimated at about 70 million, which I assume to be a rather conservative assessment), would provide a challenge to any health care system.
On the obesity front, things are a lot less rosy, given that (as everywhere else) obesity has yet to receive the same level of professional attention and expertise afforded to diabetes or other chronic diseases.
Thanks again to the organisers for inviting me to this exciting meeting and congratulations on an excellent event that bodes well for the 2nd Conclave planned for 2018.
Just imagine if the question in the title of this post was, “Why would anyone want access to prescription medications for diabetes?” (or heart disease? or lung disease? or arthritis? or, for that matter, cancer?)
Why would anyone even ask that question?
If there is one thing we know for sure about obesity, it is that it behaves just like every other chronic disease.
Once you have it (no matter how or why you got it) – it pretty much becomes a life-long problem. Our bodies are so efficient in defending our body fat, that no matter what diet or exercise program you go on, ultimately, the body wins out and puts the weight back on.
In those few instances where people claim to have “conquered” obesity, you can virtually bet on it, that they are still dealing with keeping the lost weight off every single day of their life – they are not cured, they are just treated! Their risk of putting the weight back on (recidivism) is virtually 100% – it’s usually just a matter of time.
Funnily enough, this is no different from people trying to control any other chronic disease with diet and exercise alone.
Take for e.g. diabetes. It is not that diet and exercise don’t work for diabetes, but the idea that most people can somehow control their diabetes with diet and exercise alone is simply not true. No matter what diet they go on or what exercise program they follow, sooner or later, their blood sugar levels go back up and the problems come back.
You could pretty much say the same for high blood pressure or cholesterol, or pretty much any other chronic health problem (that, in fact, is the very definition of “chronic”).
So why medications for obesity?
Because, like every other chronic disease, medications can help patients achieve long-term treatment goals (of course only as long as they stay on treatment).
Simply put, if the reason people virtually always regain their lost weight (no matter how hard they try to lose it) is simply because of their body’s ability to resist weight loss and promote weight regain, then medications that interfere with the body’s ability to resist weight loss and promote weight regain, will surely make it far more likely for them to not only lose the weight but also keep it off.
Now that we increasingly understand many of the body’s mechanisms to defend against weight loss and promote weight regain (and the body has a whole bag of tricks that you are up against), then pharmacologically blocking these mechanisms makes this a manageable (fair?) fight.
This is by no means easy. Interfering with human physiology always comes at a cost – which is why we need medications that are robustly tested for safety and efficacy (which is why we are here talking about prescription medications and not the nonsense you can buy over the counter in your local drug store or health supplement outlet).
There is of course no guarantee that any one medication will work for or be tolerated by everyone – again, no different from the medications for other chronic diseases (which is why we have so many of them for the same indication).
So who has access to prescription anti-obesity medications in Canada?
Short answer – almost no one.
Thus, in the 2017 Report Card on Access To Obesity Treatment For Adults, released last week at the 5th Canadian Obesity Summit, the less than 20% of Canadians living with obesity (and that is a very generous estimate) have access to the two prescriptions medications approved by Health Canada for long-term treatment of obesity.
Thus, as far a coverage for obesity medications in Canada is concerned,
Neither anti-obesity medication (Xenical® or saxenda®) are listed as a benefit on any provincial/territorial formulary and, therefore, they are not covered under any provincial public drug benefit (or pharmacare) programs.
There may be special-access programs in some provinces that adjudicate coverage for non-formulary medications based on individual case review; however, coverage for anti-obesity medications through these programs are not guaranteed and are, in fact, rare.
Anti-obesity medications are not covered in any federal public drug benefit programs.
Again one must ask, what will it take for governments, employers, and payers to stop discriminating against Canadians living with obesity in our healthcare system?
Disclaimer: I have received honoraria for speaking and consulting for companies that make anti-obesity medications